Upstream eventInduction, CYP1A2/CYP1A5
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to uroporphyria||adjacent||Moderate||Low|
Life Stage Applicability
Key Event Relationship Description
The oxidation of uroporphorynogen to its corresponding porphyrin (UROX) is preferentially catalyzed by the phase one metabolizing enzyme, CYP1A2, in mammals and CYP1A5 in birds. Uroporphyrinogen, an intermediate in heme biosynthesis, is normally converted to coproporphyrinogen by uroporphyrinogen decarboxylase (UROD); induction of CYP1A2 expression translates to increased protein levels and therfore an increased incidence of binding, and oxidation of uroporphyrinogen, preventing its normally dominant conversion to coproporphyrinogen.
Evidence Supporting this KER
WOE for this KER is moderate.
Include consideration of temporal concordance here
UROX activity is increased by inducers of the CYP1A subfamily and inhibited by substrates of CYP1A2, indicating that uroporphorynogen binds to the active site of CYP1A2. Furthermore, mice with a higher endogenous level of CYP1A2 are more susceptible to porphyrin accumulation and CYP1A2 knock-out prevents chemical-induced uroporphyria all-together; therefore, CYP1A2 is essential for UROX. A mild porphyric response was observed in the presence of iron loading and 5-aminolevulinic acid (ALA; a heme precursor) in AHR-/- mice, indicating that CYP1A2 induction is not absolutely necessary, but that constitutive CYP1A2 levels are sufficient for UROX under certain conditions.
Uncertainties and Inconsistencies
Although CYP1A2 plays an essential role in UROX in animal models of porphyria, it seems to be less significant in human development of porphyria cutanea tarda. UROX activity in human liver microsomes was not correlated with CYP1A2 content. Experiments with different expression systems confirmed that human CYP1A2 catalyzes UROX, but with a lower specific activity than that of the mouse orthologue.
It is also worth noting that there exists a secondary, CYP1A2-independent pathway to UROX that is hypothesized to depend solely on iron. Phillips et al. were able to generate uroporphyria in a Cyp1A2-/- mouse model that is genetically predisposed (Hfe-/-, Urod-/+) to develop porphyria in the absence of external stimuli; CYP1A2 knockout alone prevented porphyrin accumulation, but with the addition of iron and ALA to the triple knockout, modest porphyria was observed. Therefore, under extreme porphyric conditions, UROX can occure in the absence of the CYP1A2 enzyme.
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
UROX is positively correlated with CYP1A2/5 activity but this relationship has not been quantitatively describes. It has been noted however, that a CYP1A2 induction of just 2-fold dramatically induces porphyrin accumulation in iron-loaded mice.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- ↑ 1.0 1.1 1.2 1.3 Jacobs, J. M., Sinclair, P. R., Bement, W. J., Lambrecht, R. W., Sinclair, J. F., and Goldstein, J. A. (1989). Oxidation of uroporphyrinogen by methylcholanthrene-induced cytochrome P-450. Essential role of cytochrome P-450d. Biochem. J 258 (1), 247-253.
- ↑ 2.0 2.1 2.2 2.3 Lambrecht, R. W., Sinclair, P. R., Gorman, N., and Sinclair, J. F. (1992). Uroporphyrinogen oxidation catalyzed by reconstituted cytochrome P450IA2. Arch. Biochem. Biophys. 294 (2), 504-510.
- ↑ 3.0 3.1 3.2 Sinclair, P. R., Gorman, N., Walton, H. S., Sinclair, J. F., Lee, C. A., and Rifkind, A. B. (1997). Identification of CYP1A5 as the CYP1A enzyme mainly responsible for uroporphyrinogen oxidation induced by AH receptor ligands in chicken liver and kidney. Drug Metab. Dispos. 25 (7), 779-783.
- ↑ 4.0 4.1 Elder, G. H., and Roberts, A. G. (1995). Uroporphyrinogen decarboxylase. J Bioenerg. Biomembr. 27 (2), 207-214.
- ↑ 5.0 5.1 Gorman, N., Ross, K. L., Walton, H. S., Bement, W. J., Szakacs, J. G., Gerhard, G. S., Dalton, T. P., Nebert, D. W., Eisenstein, R. S., Sinclair, J. F., and Sinclair, P. R. (2002). Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron. Hepatology 35 (4), 912-921.
- ↑ Greaves, P., Clothier, B., Davies, R., Higginson, F. M., Edwards, R. E., Dalton, T. P., Nebert, D. W., and Smith, A. G. (2005) Uroporphyria and hepatic carcinogenesis induced by polychlorinated biphenyls-iron interaction: absence in the Cyp1a2(-/-) knockout mouse. Biochem. Biophys. Res. Commun. 331 (1), 147-152.
- ↑ Sinclair, P. R., Gorman, N., Dalton, T., Walton, H. S., Bement, W. J., Sinclair, J. F., Smith, A. G., and Nebert, D. W. (1998) Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice. Biochem. J. 330 ( Pt 1), 149-153.
- ↑ Smith, A. G., Clothier, B., Carthew, P., Childs, N. L., Sinclair, P. R., Nebert, D. W., and Dalton, T. P. (2001) Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 173 (2), 89-98.
- ↑ Davies, R., Clothier, B., Robinson, S. W., Edwards, R. E., Greaves, P., Luo, J., Gant, T. W., Chernova, T., and Smith, A. G. (2008) Essential role of the AH receptor in the dysfunction of heme metabolism induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chem. Res. Toxicol. 21 (2), 330-340.
- ↑ Sinclair, P. R., Gorman, N., Tsyrlov, I. B., Fuhr, U., Walton, H. S., and Sinclair, J. F. (1998b). Uroporphyrinogen oxidation catalyzed by human cytochromes P450. Drug Metab Dispos. 26 (10), 1019-1025.
- ↑ 11.0 11.1 11.2 Phillips, J. D., Kushner, J. P., Bergonia, H. A., and Franklin, M. R. (2011) Uroporphyria in the Cyp1a2-/- mouse. Blood Cells Mol. Dis. 47 (4), 249-254.
- ↑ van Birgelen, A. P., DeVito, M. J., Akins, J. M., Ross, D. G., Diliberto, J. J., and Birnbaum, L. S. (1996). Relative potencies of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls derived from hepatic porphyrin accumulation in mice. Toxicol. Appl. Pharmacol. 138 (1), 98-109.